Establishing and maintaining effective humoral immunity is an important aspect of healthy aging and the goal of most vaccines. Substantial evidence from multiple laboratories has agreed that long-lived humoral immunity derives from long-lived plasma cells that reside in the bone marrow. Plasma cells have been defined as the ultimate protein synthesis factories, secreting an estimated 1000 molecules of antibody/sec, and some investigators make a compelling argument that the only recourse for a plasma cell is a short lifespan, limited by oxidative and proteosomal stress. Thus, a fundamental issue is how do long-lived plasma cells survive for years and maintain high levels of protein production? Most cells use aerobic respiration, which is generally associated with cell damage, senescence, and death. In this pilot application, we propose that some long-lived, bone marrow plasma cells adapt to the increased demand in energy and synthesis by employing a different metabolic strategy in order to deal with the cellular and metabolic stresses. Our preliminary data indicate metabolic and cell surface phenotypic heterogeneity among resident bone marrow plasma cells, which can be discriminated as three subpopulations. Goal 1 will first address the metabolic characteristics of newly-made and resident bone marrow plasma cells that accumulate stably within the bone marrow after antigen-specific immunization. Goal 2 is designed as a preliminary investigation to understand how the metabolic phenotype of long-lived plasma cell subsets relates to their turnover and longevity. The experimental design incorporates single cell resolution in order to understand the possible heterogeneity of long-lived plasma cells. When complete, these studies will provide a deeper understanding of the cellular metabolic characteristics of long-lived bone marrow plasma cells. The results will provide an experimental foundation for new hypotheses to explain the apparent unique adaptation for long term survival in an energetically demanding process.